Formyl peptide receptor (FPR) belongs to the family of G-protein coupled receptors (GPCRs). The FPR family can be divided into three classes, FPR1, FPR2 and FPR3. FPR2 and FPR3 are classified into FPR-like receptors, wherein FPR2 is also known as FPR-like receptor 1 (FPRL-1) and FPR3 is also known as FPR-like receptor 2 (FPRL-2). FPR1 is found in monocytes, polymorphonuclear leukocytes and immature dendritic cells, and FPR2 is found in liver cells, lung cells, spleen cells, T lymphocytes, monocytes and polymorphonuclear leukocytes. FRP1 and FPR2 are two members of the FPRs, which are found in human neutrophils. Formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP or fMLF) is a N-formyl peptide, which is a chemo-attractant bound to FPR1 and further to trigger a cell activating response to release toxic substances or proteases. The affinities of fMLF toward the three FPR receptors are different, and the affinity is higher for FPR1. The activation of FPR1 elicits multiple signaling pathways, such as calcium, phospholipase C, phosphatidylinositol 3-kinase (PI3K), mitogen-activated protein kinases (MAPKs), and protein tyrosine kinases (PTKs), which cause neutrophils activation for migration, respiratory burst, and degranulation. Thus some literature reported that inhibition of activation of neutrophils could be as target for treatment of inflammation induced by neutrophils, such as asthma, rheumatoid arthritis, psoriasis, sepsis, myocardial ischemia/reperfusion injury, acute respiratory distress syndrome, chronic obstructive pulmonary disease, etc. Recent studies indicated that FPR1 is not only involved in infection and the inflammatory process, but also playing a role in promoting tumor progression. In particular, FPR1 is able to interact with endogenous annexin AI, and then transactivate EGFR in glioblastoma cells to mediate cell migration and growth. Therefore, FPR1 also is a therapeutic target for treating human glioblastoma.
In 2010, Movitz and his co-workers showed that a peptide with a Trp-Phe fragment in the C-terminal was able to selectively bind to the FPR1 receptor; however, this dipeptide alone was unable to inhibit the neutrophil respiratory burst induced by FMLP, and the associated generation of superoxide anion (O2.−) or radicals.
Additionally, a search Orbit and Google patent databases, EP 2490021 A1 and WO 2012112048 A1 recited a series of dipeptide derivatives containing chemical formulas such as H—X1—X2—OH, which can be used as pattern recognition receptors and the signal transduction pathway for G-protein coupled receptors, wherein configurations of two amino acids are both S (or R) configurations.
US 20130109866 A1 and WO 2013062947 A1 disclose that a series of derivatives of N-terminal amino acids containing urea groups can regulate a FPRL-1 receptor, which is an alias for an FPR2 receptor.
WO 2012074785 A1, WO 2013070600 A1, U.S. Pat. No. 8,440,684 B2, WO 2013009543 A1, US 20120238628 A1, US 20110319454 A1 and WO 2012109544 A1 all disclose technical solutions for regulating compounds about FPRL-1 receptors.
Based on the above, FPR1 antagonists can regulate inflammation, cancers and other diseases, but no FPR1 antagonist is used clinically. Therefore, the development of an FPR1 antagonist is currently very important.